The overall goal of this program is to develop new methods for the synthesis of nitrogen-containing molecules of biomedical interest. This work has focused on techniques for the introduction of a substituted nitrogen atom via new reactions of alkyl azides that are closely related to the classical Schmidt reaction of hydrazoic acid. It is our intention to develop new aspects of these methods that will extend their reach and deepen our understanding of the mechanistic principles underlying them. The utility of these techniques for nitrogen introduction will be demonstrated in the context of alkaloid total synthesis. These projects allow us to examine our new methodologies in the challenging context of "real-world" targets and to develop new techniques as specific problems arise. The specific aims of the present proposal are: Specific Aim 1: Examine New Aspects of Alkyl Azide Chemistry. The main subgoals during the proposed funding period will be to (a) investigate reactions that lead to bridged bicyclic amides or derivatives thereof, (b) explore the reactions of azides with oxyallyl cations, such as those derived from cyclopropanone ketals, (c) develop the vinylogous Schmidt reaction of alkyl azides, and (d) look into possible modes of stereocontrol in the reactions of alkyl azides with ketones. Specific Aim 2. Extend the Utility of in Situ Tethering in Heterocycle Synthesis. This section of the proposal concerns the continued development, and stereochemical investigation of the reactions of ketones with hydroxyalkyl azides (the Boyer reaction) and the manipulation of the resulting iminium ethers. Specifically, this entails the continued exploration of asymmetric lactam synthesis by (a) experimental and (b) computational means, as well as experiments that address (c) the kinetic resolution of lactams and (d) the continued development of the three-component coupling reaction. Specific Aim 3. Synthesize Stenine and Stemspironine. Specific Aim 4. Synthesize the Dendrobatid Alkaloid 251F. Specific Aim 5. Synthesize Cylindricine C.